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Regulation of signaling pathway, cell cycle, and cell growth in atherosclerosis

动脉粥样硬化信号通路、细胞周期和细胞生长的调节

基本信息

批准号：
13470221
负责人：
YAMADA Nobuhiro
金额：
$ 9.15万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470221/
关键词：
Atherosclerosis cell cycle CDK inhibitor cell differentiation アポトーシスシグナル伝達

项目摘要

There is an increasing demand to investigate the mechanisms of the formation of atherosclerosis, as diseases due to vascular complications of diabetes, hyperlipidemia and hypertension is rapidly increasing in Japan according to the recent changes in life style. Deregulation of the growth and apoptosis of vascular endotherial cells and smooth muscle cells are believed to play important roles in the formation of atherosclerosis. Therefore, it is important to study the controls of signal transduction and cell cycle of these cells during this process, which may lead to a development of the way of prevention. We have discovered the p27 CDK inhibitor, an apparent brake of the cell cycle, and have shown that CDK inhibitors, including p27, may play important roles in the regulation of cell differentiation and proliferation. Using vascular endotherial cell, we have shown that the two CDK inhibitors, p21Cip1 and p27Kip1, may have different roles in the regulations of apoptosis of the cell by the TNF-a stimuli. In the presence of insulin in the culture medium, TNF-a induced p27, where without insulin, TNF-a decreased p27 and induced p21. Apoptosis was induced more efficiently with the cells untreated with insulin, therefore, it is likely that p27 may have suppressive role, where p21 may induce apoptosis. As apoptosis of the endotherial cells are important in the formation of atherosclerotic changes, CDK inhibitors may be utilized in the prevention. Progression of atherosclerosis may be induced through a vicious cycle composed of a combination of cytokines, chemokines, adhesion molecules and extracellular matrix locally expressed by macrophage, lymphocyte, endotherial cell and smooth muscle cells. Therefore, we will investigate the effect of these molecules on the apoptosis of endotherial cells to seek for the way to prevent atherosclerosis.

研究动脉粥样硬化形成机制的需求日益增加，因为根据最近生活方式的变化，日本由糖尿病、高脂血症和高血压引起的血管并发症正在迅速增加。血管内皮细胞和平滑肌细胞的生长和凋亡被认为在动脉粥样硬化的形成中起重要作用。因此，研究这一过程中这些细胞的信号转导和细胞周期的控制是很重要的，这可能会导致预防方法的发展。我们已经发现了CDK抑制剂p27，一个明显的细胞周期刹车，并表明CDK抑制剂，包括p27，可能在调节细胞分化和增殖中发挥重要作用。利用血管内皮细胞，我们发现两种CDK抑制剂p21Cip1和p27Kip1可能在TNF-a刺激下调控细胞凋亡中具有不同的作用。在有胰岛素的培养基中，TNF-a诱导p27，而在没有胰岛素的培养基中，TNF-a降低p27并诱导p21。未经胰岛素处理的细胞更有效地诱导细胞凋亡，因此，p27可能具有抑制作用，而p21可能诱导细胞凋亡。由于内皮细胞的凋亡在动脉粥样硬化改变的形成中起重要作用，CDK抑制剂可用于预防。动脉粥样硬化的进展可能是由巨噬细胞、淋巴细胞、内皮细胞和平滑肌细胞局部表达的细胞因子、趋化因子、粘附分子和细胞外基质共同作用形成的恶性循环。因此，我们将研究这些分子对内皮细胞凋亡的影响，寻求预防动脉粥样硬化的方法。